1. Field of the Invention
The cephalosporin derivatives of the present invention possess in general the usual attributes of that family of antibacterial agents and are particularly useful in the treatment of bacterial infections by injection.
2. Description of the Prior Art
Derivatives of various .alpha.-amino penicillins and cephalosporins with nitro-substituted heterocyclic aldehydes are described in U.K. Pat. No. 1,311,498. Reaction products of various .alpha.-amino penicillins and/or cephalosporins with formaldehyde are disclosed in South African Pat. No. 72/8475 (see U.K. Pat. No. 1,401,285), with acetaldehyde in South African Pat. No. 72/8474 (See U.K. Pat. No. 1,389,540) and with various aldehydes and ketones in South African Pat. No. 72/8476 (See U.K. Pat. No. 1,388,400).
Derivatives of cephalosporins having in the acylamido group at the 7-position an .alpha.-amino group which has been reacted with an aldehyde are disclosed in U.S. Pat. No. 3,880,842; U.S. Pat. No. 3,887,546 and Farmdoc 49804W.
The reaction products of acetone with various .alpha.-amino cephalosporins are disclosed in the patent literature as follows:
1. with cephaloglycin, in U.S. Pat. No. 3,303,193; PA1 2. with cephalexin, in U.S. Pat. No. 3,714,146 and U.K. Pat. No. 1,314,758 and U.S. Pat. No. 3,780,028; PA1 3. with 7-[.alpha.-amino-(2'-thienyl)acetamido]-cephalosporanic acid, in U.S. Pat. No. 3,311,621; PA1 4. with certain ring-substituted cephaloglycins in U.S. Pat. No. 3,464,985; and PA1 5. with certain ring-substituted cephalexins and cephaloglycins, in U.S. Pat. Nos. 3,489,750; 3,489,751 and 3,489,752. PA1 R.sup.1 is hydrogen, sodium or potassium, PA1 R.sup.2 is carboxyl or 2-furyl or an aliphatic, aromatic or heterocyclic radical to which there is also attached a strongly acidic group in the form of its sodium or potassium salt, and PA1 R.sup.3 is tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl or 1,2,4-triazol-5-yl, each of such groups being unsubstituted or substituted with one or two lower alkyl groups of one to four carbon atoms. In the preferred embodiments the carbon atom attached to the benzene ring (para to the hydroxyl group) has the D configuration. PA1 R.sup.1 is hydrogen, sodium or potassium, PA1 R.sup.2 is carboxyl or 2-furyl or an aliphatic, aromatic or heterocyclic radical to which there is also attached a strongly acidic group in the form of its sodium or potassium salt, and PA1 R.sup.3 is tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl or 1,2,4-triazol-5-yl, each of such groups being unsubstituted or substituted with one or two lower alkyl groups of one to four carbon atoms which comprises PA1 1. forming a suspension of the amphoteric cephalosporin or a solvate or hydrate thereof in a suitable inert organic solvent, said solvent being a solvent for the triethylamine salt of the aldehyde reaction product of the amphoteric cephalosporin and a non-solvent for the alkali metal salt of formula I; PA1 2. treating the suspension with the aldehyde and sufficient triethylamine to form in solution the triethylamine salt of the aldehyde reaction product of the amphoteric cephalosporin; and PA1 3. precipitating the desired alkali metal salt of formula I from the solution by adding a solvent-soluble sodium or potassium base. PA1 West Germany Pat. No. 2,404,592 (Farmdoc 57268V) PA1 1. Slurry 1 gram of BL-S643.3H.sub.2 O in 10 ml. of water at 40.degree.-45.degree. C. PA1 2. add 0.25 gram (1.25 equivalents) of 2-furaldehyde. PA1 3. Add 1N sodium hydroxide with rapid stirring to pH 7-7.5. A solution or near solution is obtained in under 5 minutes. PA1 4. Cool the solution to 22.degree.-24.degree. C. and suitably filter to remove particles, bacteria and pyrogens. PA1 5. Lyophilize under sterile conditions for 48 hours to obtain BL-S1057 powder (BL-S1057 may also be obtained by precipitation of the sterile solution of step 4 with 15 to 20 volumes of sterile isopropanol). PA1 a. Bio-assay (using cefatrizine as the standard) = 759 mcg./mg. PA1 b. IR = Intact .beta. lactam; well-defined PA1 c. NMR = PA1 d. Solubility = &gt;400 mg./ml. in water PA1 e. Paper strip chromatography = Primarily 1 zone at R.sub.f of BL-S643 at 37.degree. C. at 0 and 1 hour (concentration = 0.2 mg./ml.) PA1 f. Liquid chromatography = 100% hydrolyzed in pH 6.1 buffer within 1 hour at room temperature (concentration = 1 mg./ml.) PA1 g. MP = 180.degree. C. (shrink) - 200.degree. C. decomposes PA1 1. slurry 0.45 gram of 5-formyl-2-furansulfonic acid sodium salt ##STR11## in 10 ml. of water at 40.degree.-45.degree. C. A solution or near solution is obtained. PA1 2. Sprinkle in 1 gram of BL-S643.3H.sub.2 O over a 10 minutes period with rapid stirring and concomitant addition of 1N sodium hydroxide to pH 7-7.5. A solution or near solution is obtained within 5 minutes. PA1 3. Cool to 20.degree.-23.degree. C. and pass the solution through suitable filters to remove particles, bacteria and pyrogens. PA1 4. Lyophilize for 48 hours. The resulting powder is BL-S1058 (sterile BL-S1058 may also be obtained from the solution of step 3 by precipitation from 15-20 volumes of sterile isopropanol). PA1 a. Bio-assay (using cefatrizine as the standard) = 685 mcg./mg. PA1 b. IR - NMR = PA1 1. well-defined; consistent PA1 2. .beta.-lactam and 3-side chain intact PA1 3. 90% cyclic adduct (at approximately 60 mg./ml. in D.sub.2 O). PA1 c. Paper strip chromatography = Primarily 1 zone at R.sub.f of BL-S643 at 0 and 1 hour at 37.degree. C. (concentration is 0.2 mg./ml.) There is evidence of a second zone. PA1 d. Liquid chromatography (1 mg./ml. in pH 6 buffer)
More distantly related are the intermediates produced when a cephalosporin nucleus, e.g. 7-ACA or 7-ADCA, is acylated with a reactive derivative of an .alpha.-amino acid in which the .alpha.-amino group has been protected by prior reaction with a .beta.-diketo compound such as methyl acetoacetate, methyl acetoacetamide or acetylacetone; these are exemplified by Farmdoc 22850W and 60669V.
In the penicillin field the penicillins containing an .alpha.-amino group in the 7-acylamido substituent, e.g. ampicillin, with ketones and aldehydes were apparently first disclosed by Johnson et al. (U.S. Pat. No. 3,198,804) and Granatek (U.S. Pat. No. 3,198,788). Similar reaction products made from various such penicillins by reaction with the same or different aldehydes and ketones were later reported in U.S. Pat. Nos. 3,230,214, 3,316,247 (diketones), 3,325,479 (diketones), 3,489,746, 3,549,746, 3,558,602, 3,635,953, 3,641,000, 3,647,781 (which includes some cephalosporins), 3,725,389, 3,780,028 3,784,562 (diketone), 3,886,140, 3,888,848, 3,905,955 and 3,904,604 and U.K. Pat. No. 1,267,936.